Plenty, considering the reality and the reactions to a study published in a recent issue of Lancet Infectious Diseases on the emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK. [1] The resistance mechanism at the center of the storm is the New Delhi Metallo beta-lactamase (NDM), a novel metallo beta-lactamase (MBL) coded by a novel gene bla(NDM-1). MBLs are enzymes that mediate resistance to almost all beta lactam agents (except monobactams) including the most effective and stable of these, viz., carbapenems. [2] The article in question studied carbapenem resistant clinical isolates belonging to enterobacteriaceae family (such as Escherichia More Details coli and Klebsiella pneumoniae) from two Indian centers, one from Chennai and the other from Haryana, and those referred to UK national reference laboratory from different sites within and outside UK, to detect the presence of the novel carbapenem resistance gene. Not only was this novel gene detected in E. coli and Klebsiella isolates from India but also it was found that the strains carrying this gene demonstrated multidrug resistance being susceptible only to tigecycline and colistin. More worrisome is the finding that the isolates from Chennai and Haryana were primarily from community acquired urinary tract infections, pneumonia, and blood-stream infections. The report also found that many of the UK NDM-1 positive patients had traveled to India or Pakistan within the past year, or had links with these countries, an observation which many felt was unsubstantiated to assume a direct correlation. [3],[4]

Until recently, MBLs have been associated mainly with the non-fermentative Gram negative bacilli such as Pseudomonas aeruginosa. [2] They did not receive stormy attention since non-fermenters are known to be problem pathogens due to their inherent high level resistance. Between the two groups, non-fermenters and enterobacteriaceae, the latter are considered safer to harbor because of their better susceptibility profile. However, with the increasing prevalence of extended spectrum beta lactamase (ESBL) producing enterobacteriaceae [5],[6] and the subsequent increase in the use of carbapenems, the development of carbapenem resistance in enterobacteriaceae was an eventuality. Carbapenem resistance can be mediated by either carbapenemases or MBLs or by efflux mechanisms or by loss of outer membrane proteins. [7] Carbapenemase producing enterobacteriaceae are being increasingly reported since the last few years, such as in K. pneumoniae. [5],[8] Termed Klebsiella pneumoniae carbapenemase (KPC), it is currently a global problem and is also being reported in other Gram negative bacilli. Patients harboring highly resistant organisms, such as those elaborating ESBL or carbapenem hydrolyzing enzymes, are more likely to develop complications or have a higher risk of mortality. [9]

NDM-1 is a novel MBL found in enterobacteriaceae. It was first reported in a Swedish patient of Indian origin, a diabetic male, who returned to Sweden after having received treatment at a hospital in New Delhi for gluteal abscess in December 2007. [10] In January 2008, the patient visited a Swedish hospital where a K. pneumoniae carrying the novel MBL was isolated from his urine. The MBL identified in this patient was different from the previous MBLs described, harboring a gene for a new MBL, and therefore novel, and since the immediate previous treatment was traced to New Delhi, it was probably named as NDM-1. Two aspects should raise concern about this phenomenon. One is that this difficult to treat resistance mechanism was observed in enterobacteriaceae, the commonest normal intestinal flora. Two, this new NDM gene is carried on plasmids and on a cassette which means that they can theoretically move as independent entities and be freely exchanged. These two reasons are sufficient to make this a major community acquired problem if not sufficiently addressed. Since its "discovery", NDM-1 has been reported in other members of the enterobacteriaceae family, such as E. coli, Citrobacter freundii, Morganella morganii and Enterobacter cloacae. [11] Carbapenem resistant enterobacteriaceae have been reported from other studies in India, [12],[13] including a report on NDM-1 enterobacteriaceae from Mumbai. [14]

Antimicrobial resistance is a growing problem and is likely to become worse. Based on published literature, it appears that resistance rates in Gram negative bacilli are higher in India and Asia as compared to the west. [6],[15] Urgent measures are called for to control this trend. Even though the Indian origin of this novel resistance has been questioned, [3],[4] everyone should take this as a wake-up call. Health administrators should initiate strategies that would blunt the developing resistance curve. Everyone should wake up to the judicious use of antibiotics. This would require an interaction between all stakeholders getting together on a common platform to decide on appropriate antimicrobial use. It would require putting a stop to the unethical and unsubstantiated marketing practices of pharmaceutical industries. It would also require the development and implementation of national guidelines or legislation to prevent and control health care associated infections and the inclusion of health care associated infections as a separate subject for examination to be taught to all postgraduate students irrespective of their subject of specialization. In addition, it would require putting an end to the "over-the-counter" availability of antibiotics.

The clinical microbiology laboratories should screen isolates with near susceptible or resistant carbapenem zone diameters or minimum inhibitory concentration (MIC) values for KPC and other carbapenemases or MBL production using simplified phenotypic tests such as modified Hodge test and Imipenem EDTA test. Today most reports on antimicrobial resistance, whether novel or known, are from centers which are primarily tertiary care centers. In order to understand the problem at a national level, a three-tier system for antimicrobial resistance surveillance can be developed with the centers at first tier (those without a microbiology laboratory and a qualified microbiologist) collecting specimens to send to laboratory as a second tier (having the capacity to perform culture, antibiotic susceptibility test and detect resistance mechanism using phenotypic methods) and national or regional level reference laboratories as the third tier, carrying out molecular surveillance for the known and novel resistance genes.

Clinicians have an important role to play in delaying the development of resistance by only treating bacterial infections with antibiotics, treating infections and not colonization, and using carbapenems and polymyxins extremely judiciously.

Does all resistance emerge de novo? Just a small percentage occurs. A majority of resistance is acquired under selection pressure. It is subsequently horizontally transferred between bacteria or between patients as a consequence of poor health care delivery. When pan drug resistant pathogens are isolated, these patients should be strictly isolated and contact precautions should be put into practice. Considering the burden on public health care delivery systems with space constraints, this seems practically difficult. However, it is important to implement even if it requires repeated cerebral conditioning, especially if one visualises the subsequent eventuality. Unless concerted efforts are made, it will not be long before resistance is reported to the last antimicrobials currently standing the onslaught of Gram negative bacterial resistance, namely, polymyxins and tigecycline.

The documentation of the presence of this novel resistance mechanism in organisms as ubiquitous as E. coli and K. pneumoniae is a cause for serious concern and calls for immediate corrective and preventive measures. Reducing or delaying the development of resistance is the need. This requires the immediate and compulsory implementation of an institutional antibiotic policy to prevent the situation from getting out of control, a measure known to be effective. [16] Additional measures as described above will help control not only just the rise and spread of NDM but also the rise and spread of any resistance.